Evaluation of treatment and outcome for patients with haemophilia A and haemophilia B on extended half-life (EHL) factor products: A 12-month data analysis.

INTRODUCTION: Extended half-life (EHL) factor VIII and IX concentrates as prophylaxis against bleeds have been available to selected persons with haemophilia (PWH) in Australia since March 2018. Preliminary analysis of switching to EHL demonstrated increased treatment adherence, fewer injections and improved bleeding outcomes. AIMS: To characterise clinical practices regarding the use of EHL in Australia, to further evaluate treatment regimens and bleeding outcomes, and to analyse the influence of EHL product pharmacokinetics on clinical decision-making. METHODS: A national, retrospective study was conducted using the Australian Bleeding Disorders Registry (ABDR). Patients on EHL products during the entire 2019 calendar year were included for analysis. RESULTS: A complete and validated dataset of 174 PWH was analysed, 115 Haemophilia A (HA) and 59 Haemophilia B (HB). Adherence to EHL therapy was 85.7% in HA and 87.2% in HB. About 63.5% of HA and 64.4% of HB PWH reported zero spontaneous bleeds over 12months. Ankles were the most frequent spontaneous bleed site. Approximately one-third patients underwent dose adjustments, with most frequent reasons being pharmacokinetics, body weight change and breakthrough bleeds. About 19.5% of PWH had target joint history, with spontaneous bleeds reported in 58% of that cohort on EHL. Multivariate regression showed significant impact of non-adherence, target joint history and short half-life on spontaneous bleeds in the HA cohort; however only short half-life had significant impact in the HB cohort. CONCLUSION: EHL usage in Australia shows excellent treatment adherence and bleeding outcomes. This study affirms the use and value of widely available population-based pharmacokinetics as a clinical tool.

Haemophilia joint health score (HJHS) usage, patterns and outcome data in patients with haemophilia A and haemophilia B in Australia: A descriptive study using the Australian Bleeding Disorders Registry (ABDR).

INTRODUCTION: Assessment of joint health is an essential component of haemophilia management. A variety of clinical tools have been developed to standardise this assessment process. One such tool, the Haemophilia Joint Health Score (HJHS), is embedded for use within the Australian Bleeding Disorders Registry (ABDR). This provides a unique opportunity to analyse patterns of tool usage as well as associations between scores, demographics and clinical outcome factors. AIMS: To characterise clinician practices regarding use of HJHS in routine clinical assessment of persons with haemophilia (PWH), to examine relationships between HJHS, and age, inhibitor status and body mass index (BMI), and to identify potential barriers to HJHS tool usage. METHODS: A national, retrospective study was conducted using data extracted from the ABDR between 2014 and 2020, complemented by a qualitative questionnaire exploring haemophilia treatment centre (HTC) structure, resourcing and clinician perspectives about HJHS. RESULTS: 28.1% (622/2220) of PWH had at least one HJHS recorded in the ABDR during the defined study period (546 haemophilia A, 76 haemophilia B). HJHS were recorded more in children than adults and performed more in severe than non-severe haemophilia. Multivariate analysis demonstrated significant association of age, severity and inhibitor status with HJHS. No association was identified between BMI and HJHS. Qualitative surveys revealed significant variation in physiotherapy funding, availability and methods of tool use between HTCs. CONCLUSION: This study provides valuable insights into joint health assessment in Australia. It improved our understanding of factors influencing long-term joint outcomes. Practical limitations of HJHS tool were also discussed.

The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder.

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.

NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum.

BACKGROUND: The nucleotide binding protein-like (NUBPL) gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have NUBPL disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families). METHODS: Whole exome sequencing was used to identify patients with compound heterozygous NUBPL variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model (Yarrowia lipolytica) and mitochondrial respiration experiments on patient fibroblasts. RESULTS: The previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found in cis with c.815-27T>C, but only two of four families had both variants. The second variant found in trans with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3-18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity. CONCLUSION: We report on five new patients with NUBPL disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic NUBPL variants.

Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor.

De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome.

DLG4-related synaptopathy: a new rare brain disorder.

PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Pediatric single large-scale mtDNA deletion syndromes: The power of patient reported outcomes.

There is a limited understanding of system-level clinical outcomes and interventions associated with single large-scale mitochondrial DNA deletion syndromes (SLSMDS). Additionally, no research exists that describes patient reported outcomes (PROs) of children with SLSMDS. A global and observational registry was established to understand the multi-systemic course of SLSMDS and track clinical outcomes. The development and design of the registry is described. Demographic characteristics, history and diagnoses, and system level prevalence of problems and interventions are reported for 42 children. System level problems and interventions include information on the following body systems: audiology, cardiac, endocrine, gastrointestinal (including pancreatic and hepatobiliary system), hematological, metabolic, neurological (including autonomic, mobility, & learning), ophthalmic, psychiatric, renal, and respiratory. Results emphasize the need of patient registries and suggest that the diagnostic odyssey and burden of disease for children with SLSMDS is significant. System-level findings may help families and clinical providers with diagnosis, prognostication, and treatment. A multidisciplinary team of clinical experts with a central coordinating specialist for children with SLSMDS is recommended.

The Australian experience with switching to extended half-life factor VIII and IX concentrates: On behalf of the Australian Haemophilia Centre Directors' Organisation.

INTRODUCTION: Extended half-life (EHL) factor (F) VIII and FIX concentrates became available to selected haemophilia A (HA) and haemophilia B (HB) patients in Australia in March 2018. AIM: To determine factor utilization and bleeding outcomes during the first 6 months of prophylaxis with EHL concentrates, and compare it to the last 6 months of prophylaxis with standard half-life (SHL) concentrates. METHODS: A national, retrospective study was performed using data extracted from the Australian Bleeding Disorders Registry (ABDR). Patients with ≥3 months of EHL exposure were analysed. RESULTS: A total of 129 HA patients (86 Adynovate, 43 Eloctate) and 64 HB (Alprolix) patients were included in the study. For HA, switching to EHL FVIII resulted in decreased injection frequency (3 to 2 per week), improved 'reduced adherence' rates (18% to 7%), decreased median annualized bleeding rate (ABR; 2.0 to 0.0) and increased proportion of patients with zero bleeds (44% to 64%). Actual factor utilization increased by 20 IU/kg/wk on Adynovate and 4 IU/kg/wk on Eloctate. For HB, switching to EHL FIX resulted in decreased injection frequency (2 to 1 per week), improved 'reduced adherence' rates (35% to 11%), decreased median ABR (3.0 to 2.0) and increased proportion of patients with zero bleeds (31% to 46%). Actual factor utilization decreased by 4 IU/kg/wk. There was no clinically significant inhibitor development. CONCLUSION: Compared to SHL, EHL FVIII resulted in improved bleeding outcomes, albeit at the expense of increased factor utilization. EHL FIX resulted in improved bleeding outcomes despite decreased factor utilization.

Diagnosis of 'possible' mitochondrial disease: an existential crisis.

Primary genetic mitochondrial diseases are often difficult to diagnose, and the term 'possible' mitochondrial disease is used frequently by clinicians when such a diagnosis is suspected. There are now many known phenocopies of mitochondrial disease. Advances in genomic testing have shown that some patients with a clinical phenotype and biochemical abnormalities suggesting mitochondrial disease may have other genetic disorders. In instances when a genetic diagnosis cannot be confirmed, a diagnosis of 'possible' mitochondrial disease may result in harm to patients and their families, creating anxiety, delaying appropriate diagnosis and leading to inappropriate management or care. A categorisation of 'diagnosis uncertain', together with a specific description of the metabolic or genetic abnormalities identified, is preferred when a mitochondrial disease cannot be genetically confirmed.

Harmonizing care for rare diseases: How we developed the mitochondrial care network in the United States.

The mitochondrial medicine society (MMS) has previously highlighted the clinical landscape and physician practice patterns of mitochondrial medicine in the US and attempted to develop consensus criteria for diagnosis and management to improve patient coordinated care. Most recently, and in collaboration with US-based patient advocacy groups, we developed a clinical care network to formally unify US-based clinicians who provide medical care to individuals with mitochondrial disease; to define, design and implement best practices in mitochondrial medicine building on the current consensus guidelines and to improve patients' clinical outcomes. Here we review the steps taken in collaboration with several stakeholders to develop goals and expectations for a mitochondrial care network (MCN), criteria for MCN site selection and formal launch of the network.

CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development.

OBJECTIVE: The cyclin-dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure-free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones. METHODS: This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit. RESULTS: Ninety-two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0-11.0). Eighty-one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor-tonic-spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty-three percent of patients experienced a seizure-free period ranging from 1 to >12 months, but only 6% were still seizure-free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia. SIGNIFICANCE: The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. CVI is a common feature in CDD and is correlated with achieving fewer milestones.

Outcome measures for children with mitochondrial disease: consensus recommendations for future studies from a Delphi-based international workshop.

Although there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group. The use of sensitive and valid endpoints is essential to test the effectiveness of potential treatments. There is no consensus on which outcome measures to use in children with mitochondrial disease. The aims of this two-day Delphi-based workshop were to (i) define the protocol for an international, multi-centre natural history study in children with mitochondrial myopathy and (ii) to select appropriate outcome measures for a validation study in children with mitochondrial encephalopathy. We suggest two sets of outcome measures for a natural history study in children with mitochondrial myopathy and for a proposed validation study in children with mitochondrial encephalopathy.

A physician targeted intervention improves prescribing in chronic heart failure in general medical units.

BACKGROUND: Despite strong evidence for beta-blockers and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in chronic heart failure (CHF), they have been under-utilised especially in general medical units. We aim to evaluate the effectiveness and feasibility of a physician-targeted quality improvement intervention with education and feedback on the prescription of beta-blockers and ACEI/ARB for CHF management in an inpatient setting. METHODS: We conducted an interrupted time series study between January 2009 and February 2012. A two-stage intervention was implemented. Between November 2009 and January 2011, a structured physician-oriented education program was undertaken. From February 2011, quarterly performance feedback was provided to each medical unit by a senior clinician. Medical notes of patients admitted with CHF under general medical units before and during the intervention were prospectively audited. Main outcomes were beta-blockers and ACEI/ARB prescription rates, and 180-day readmission rates for CHF. RESULTS: Four hundred and sixty-eight patients were included in this study. Structured education program was associated with a significant rise in beta-blockers prescription rates from a baseline of 60 to 92% (p = 0.003), but a non-sustained rise in ACEI/ARB prescription. Regular performance feedback resulted in a further sustained increase in ACEI/ARB prescription rates from 62 to 93% (p = 0.028) and a positive trend for beta-blockers with rates maintained at 89%. There was a reduction in 180-day readmission rates that correlated with the improvements in beta-blocker (p = 0.030) and ACEI/ARB (p = 0.035) prescription. CONCLUSION: Implementation of a structured education program with regular performance feedback was durable and was associated with improvements in appropriate prescribing and an observed decrease in CHF-related readmissions.

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.

The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.

Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.

Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project.

OBJECTIVES: The common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research. METHODS: Nine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use. RESULTS: The NINDS Mito CDEs and supporting documents are publicly available on the NINDS CDE website ( https://commondataelements.ninds.nih.gov/ ), organized into domain categories such as Participant/Subject Characteristics, Assessments, and Examinations. CONCLUSION: We developed a comprehensive set of CDE recommendations, data definitions, case report forms (CRFs), and guidelines for use in Mito clinical research. The widespread use of CDEs is intended to enhance Mito clinical research endeavors, including natural history studies, clinical trial design, and data sharing. Ongoing international collaboration will facilitate regular review, updates and online publication of Mito CDEs, and support improved consistency of data collection and reporting.

Disparities in access to anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration.

BACKGROUND: Late neovascular age-related macular degeneration (nvAMD) is very common and causes irreversible severe visual loss unless treated swiftly with vascular endothelial growth factor (VEGF) inhibitors. Although publicly subsidized access to treatment may be inequitable, which is why we assessed treatment provision across Australia. DESIGN: Secondary analysis of Australian data. PARTICIPANTS: All Pharmaceutical Benefits Scheme (including Repatriation PBS) beneficiaries. METHODS: Treatment and incidence data were obtained from Medicare Australia, the Royal Australian and New Zealand College of Ophthalmologists, Optometry Australia, the Blue Mountains Eye Study and the Australian Bureau of Statistics. Data were mapped using geographical information software, and factors associated with treatment provision were assessed using multiple linear regression models. MAIN OUTCOME MEASURE: Unmet need (%) for anti-VEGF treatment for nvAMD. RESULTS: On average, we estimated 7316 incident cases of nvAMD not to be treated per year from 2010 to 2014 (50.1% of total). Number of ophthalmologists and optometrists (per 1000, ß = -0.024; 95% confidence interval [CI] -0.041, -0.007) and being located in remote regions (ß = 0.186; 95% CI 0.110, 0.262) were associated with percentage of untreated cases. A higher proportion of the population speaking a language other than English at home was associated in univariate analyses only (ß = 0.0015; 95% CI -0.0004, 0.0027; P = 0.007). CONCLUSION: A large proportion of incident nvAMD is not treated with anti-VEGF. Not receiving treatment is more likely in regional or remote areas and areas with fewer service providers. Not speaking English at home may further limit access. Service delivery models for more equitable service provision are needed.